Reply to Liu et al.: The Andean EGLN1 adaptive allele could be a loss of function variant that increases HIF1-α in skeletal muscle
Research Article
November 11, 2019
We commend the work of Liu et al. (1), who show that EGLN1 is mainly expressed in skeletal muscle tissue compared to numerous other tissues examined, and that the rs1769793 T allele reduces EGLN1 expression in skeletal muscle. These findings lend plausibility to the hypothesis that the EGLN1 T-allele, which is at high frequency in Peruvian Quechua and also associated with a higher VO2max in hypoxia (2), operates through effects on skeletal muscle oxygen use and metabolism. This is interesting and recalls the long-standing debate in physiology regarding the relative importance of O2 delivery versus O2 use at the tissue level as determinants of VO2max (3). Certainly, in the physiological literature on highland natives, there has been a much greater emphasis on the O2 delivery side of the equation, including blood flow, hemoglobin concentration, and mechanisms of gas exchange (4–6). The work of Liu et al. points us in the direction of O2 utilization rather than oxygen delivery for future studies on Andean natives. The finding that the rs1769793 T allele leads to reduced expression of EGLN1 also is interesting and recalls the literature on the EGLN1 gene in Tibetans. The two Tibetan EGLN1 coding sequence variants that have been associated with high-altitude adaptation have been proposed as either gain of function (7) or loss of function (8) variants. Thus, the specific functional effect of EGLN1 adaptive variation in the context of hypoxia is a question that remains unresolved. While Andean and Tibetan populations may have followed different evolutionary pathways (9), our interpretation of Liu et al.’s study is that the Andean adaptive variant is likely a loss of function variant, leading to reduced levels of EGLN1 and subsequent enhanced skeletal muscle HIF1-α transcriptional activity. This, in turn, would activate various HIF-responsive genes in the muscle with (as yet) unknown metabolic benefits during strenuous exercise in hypoxia. One issue that is unclear to us is whether Liu et al. performed their eQTLs analysis in tissues in hypoxia. If not, this would be a next logical step to really understand the impact of EGLN1 variation on Andean phenotypes.
References
1
G. Liu et al., rs1769793 variant reduces EGLN1 expression in skeletal muscle and hippocampus and contributes to high aerobic capacity in hypoxia. Proc. Natl. Acad. Sci. U.S.A. 117, 29283–29285.
2
T. D. Brutsaert et al., Association of EGLN1 gene with high aerobic capacity of Peruvian Quechua at high altitude. Proc. Natl. Acad. Sci. U.S.A. 116, 24006–24011 (2019).Correction in: Proc. Natl. Acad. Sci. U.S.A. 117, 3339 (2020).
3
P. D. Wagner, H. Hoppeler, B. Saltin, “Determinants of maximal oxygen uptake” in The Lung: Scientific Foundations, R. G. Crystal, J. B. West, E. R. Weibel, P. J. Barnes, Eds. (Lippincott-Raven, Philadelphia, PA, 1997), vol. 2, pp. 2033−2041.
4
B. D. Hoit et al., Nitric oxide and cardiopulmonary hemodynamics in Tibetan highlanders. J. Appl. Physiol. 99, 1796–1801 (2005).
5
T. S. Simonson et al., Low haemoglobin concentration in Tibetan males is associated with greater high-altitude exercise capacity. J. Physiol. 593, 3207–3218 (2015).
6
P. D. Wagner et al., Pulmonary gas exchange and acid-base state at 5,260 m in high-altitude Bolivians and acclimatized lowlanders. J. Appl. Physiol. 92, 1393–1400 (2002).
7
F. R. Lorenzo et al., A genetic mechanism for Tibetan high-altitude adaptation. Nat. Genet. 46, 951–956 (2014).
8
D. Song et al., Defective Tibetan PHD2 binding to p23 links high altitude adaption to altered oxygen sensing. J. Biol. Chem. 289, 14656–14665 (2014).
9
C. M. Beall, “Tibetan and Andean contrasts in adaptation to high-altitude hypoxia” in Oxygen Sensing: Molecule to Man, S. Lahiri, Ed. (Kluwer Academic, 2000), pp. 63–74.
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© 2020. Published under the PNAS license.
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Published online: October 27, 2020
Published in issue: November 24, 2020
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